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Hemostasis and Thrombosis Vic Vernenkar, D.O. St. Barnabas Hospital Dept. of Surgery Normal Hemostasis • A well regulated process • Maintains blood in a fluid, clot free state in normal vessels • Induces the rapid formation of a localized hemostatic plug at the site of vascular injury Thrombosis • Pathological state • Inappropriate activation of the normal hemostatic process – within the non-interrupted vascular system. • Thrombus (blood clots) formation – Blocks blood flow to vital areas Normal sequence of Hemostasis (4 steps) • 1. Arteriolar vasoconstriction (transient) – Reflex neurogenic mechanisms – Bleeding would resume after vasoconstriction if it weren’t for the activation of platelets or coagulation systems • 2. Exposure of subendothelial ECM when there is endothelial injury – ECM, especially collagen, is highly thrombogenic – Platelets adhere and become activated • Change in shape • Release of secretory products – Aggregation of platelets forms hemostatic plug – This is primary hemostasis First two steps of normal hemostasis Normal hemostasis continued • 3. Tissue factor released at the site of injury (by endothelial cells) – Works with secreted platelet factors – Activates coagulation cascade • A series of proteins where thrombin is activated • Induces further platelet recruitment and granule release – Ends in fibrin deposition – Called secondary hemostasis Normal hemostasis continued • 4. Formation of permanent plug – Prevents further hemorrhage – Polymerized fibrin and platelet aggregation – Counter regulatory mechanisms (t-PA) limit the plug to the site of the injury Steps 3 and 4 The Main Players in Hemostasis • Endothelial cells • Platelets • Coagulation cascade Endothelial Cells • Produce vWF (vonWillebrand factor) – A product of normal endothelium – found in the plasma – essential for platelet binding to collagen and other surfaces • Secrete Tissue factor – induced by cytokines (TNF, IL-1) – activates the extrinsic clotting pathway Endothelial Cells have Prothrombotic Effect • Via vWF and tissue factor • factors that depress fibrinolysis • factors needed for the clot are not destroyed before clot forms Collagen is highly thrombogenic For hemostasis For inflammation For wound healing Endothelial cells have Anti-thrombotic properties, too • Antiplatelet effects – Intact cells are barrier to subendothelial ECM – PGI-2 and NO prevent platelets from adhering • Fibrinolytic properties – Tissue type plasminogen activator (t-PA) • promotes activity to clear fibrin deposits from endothelial surfaces • Anticoagulant properties – Membrane associated molecules • Heparin like molecules and thrombomodulin – Inactivate thrombin and several coagulation factors Factors that favor or inhibit thrombosis SOooo….. • Endothelial cells modulate the balance of hemostasis • Endothelial injury is the dominant influence that leads to thrombosis Platelets • Express glycoprotein receptors on membranes. Gp Ib,IIb/IIIa • Have three types of granules – Alpha granules • Fibrinogen, fibronectin, factor V and VIII, PDGF, TGFb – Dense bodies or delta granules • ATP/ADP, ionized calcium, histamine, serotonin, epinephrine – Lysosomal granules Platelets Hyalomere and granulomere Platelets continued • Upon encountering the ECM, platelets undergo three general reactions: 1. Adhesion and shape change mediated by vWF and glycoprotein Ib 2. Secretion (release reaction) – calcium required in coagulation cascade – ADP as mediator of platelet aggregation – Surface expression of phospholipid complex • Binding site for calcium ions and coagulation factors Platelets continued • 3. Aggregation – ADP and TXA2 (vasoconstrictor thromboxane A2) are the stimuli for the formation of the primary hemostatic plug • Aspirin inhibits synthesis of TXA2 – Fused mass of platelets • Created by coagulation cascade that produces thrombin • Thrombin also converts fibrinogen to fibrin cementing platelets in place Thrombocytopenia • Spontaneous bleeding, prolonged bleeding time • Lowered platelet count – Uremia, too much aspirin and rare genetic disorders – Various marrow failure or injury • Aplastic anemia, leukemia – Sometimes immunologically mediated – Destruction of platelets by prosthetic heart valves • Bleeding into CNS a concern • Common hematologic manifestation of AIDS Coagulation Cascade • A series of conversions of inactive proenzymes to activated enzymes, – culminating in the formation of thrombin • Thrombin then coverts the soluble plasma protein fibrinogen to insoluble fibrous protein fibrin Two pathways of coagulation cascade • Intrinsic – Surface contact • Extrinsic – Tissue injury Coagulation cascade Hemophilia A (classic) is due to reduced amount or reduced activity of Factor VIII Hemophilia B (Christmas Disease) results from Deficiency of factor IX Heparin is a cofactor that Allows antithrombin III to Inactivate thrombin and Factor Xa Thrombomodulin binds To thrombin, making it An anticoagulant which Then activates antiCoagulant protein C. Protein C cleave factors Va and VIIIa Control of cascade to prevent clotting elsewhere • Antithrombins • Plasminogen– activated by heparin like plasmin system molecules on endothelial cells • Clinical administration of heparin minimizes thrombosis • Proteins C and S – Vitamin K dependent – Inactivate cofactors Va and VIIIa – Breaks down fibrin and inhibits its polymerization – Products of split fibrin are anticoagulants Conditions Causing Bleeding • Incomplete hemostasis is most common cause of bleeding. • Vitamin K deficiency – severe coagulation defect – Required for synthesis of prothrombin and factors VII, IX and X • Parenchymal diseases of the liver – Liver synthesizes several coagulation factors Hereditary deficiencies • Hemophilia A--factor VIII deficiency – Sex-linked recessive – 30% due to new mutations and don’t have family link – Hemarthroses common (spontaneous bleeding in joints) – Infuse patient with factor VIII from human blood or cryoprecipitate. – Need 100% levels preop, keep at 30% postop. • Hemophilia B--factor IX deficiency – Clinically indistinguishable from Hemophilia A – Sex-linked recessive – Need 50% preoperatively – Prolonged PTT, normal PT TX: Factor IX or FFP Von Willebrand’s Disease Von Willebrand’s Disease- Most common • • • • • congenital bleeding disorder. Types I, II, and III. PT normal PTT normal or elevated Prolonged bleeding time Type I most common (70%) with mild sx. Type III causes most bleeding • Type I and IIIreduced quantity of vWF • TX: Cryo, DDAVP • Type II- defect in vWF molecule, enough of it but doesn’t work well. TX: Cryo Platelet Disorders • Acquired-H2 blockers, heparin. • Bernard-Soulier, a Gp1b receptor deficiency (can’t bind to each other) • Uremia-Inhibits Gp1b, vWF. TX: dialysis, DDAVP, cryo, plts. • Ticlopidine- decreases ADP in platelets, prevents exposure of Gp1b/IIIa receptors. • Dipyramidoledecreases ADP induced plt aggregation. • Plavix-ADP receptor antagonist. • Pentoxifyllin- inhibits plt aggregation Platelet Disorders • Heparin induced thrombocytopenia (HIT) • Antiplatelet antibodies results in platelet destruction. • Also causes aggregation and thrombosis. • Low doses of heparin. • LMWH may have less risk. • DIC • Decreased plts, prolonged PT, PTT. • Low fibrinogen, high fibrin split products, high D-dimers • Often initiated by tissue factor. • Treat underlying cause Thrombi • Platelet aggregates • Fibrin • Trapped erythrocytes and leucocytes – Not part of this hemostatic process • This is a deep vein thrombosis – Postoperative patients confined to bed Thrombotic cycle and influences Endothelial injury is dominant influence • Heart and arterial circulation • Hypercholesteremia, cigarette smoke products • Radiation, bacterial endotoxins • Results in exposure of subendothelial collagen, adherence of platelets, release of tissue factor and local depletion of prostacyclin (antithrombin) Alterations in normal blood flow • Turbulence – injures endothelium – Atherosclerotic plaques • Stasis – Can create venous thrombi – Aneurysms cause local stasis – Deformed cells of Sickle cell anemia cause vascular occlusions Stasis and Turbulence • Disrupt laminar flow (cells in middle) • Bring platelets into contact with endothelium • Prevent dilution of activated clotting factors by fresh-flowing blood • Retard inflow of clotting factor inhibitors Hypercoagulability • Leiden Factor- 30% spontaneous venous thrombosis. • Most common congenital disorder. • Resistance to Protein C, defect on factor V • TX: heparin, warfarin. • Protein C, S deficiency-5% venous thromboses. TX: heparin, warfarin. Hypercoagulability • Antithrombin III deficiency- 2-3% thrombosis. Heparin doesn’t work. Can develop after previous heparin exposure. • TX: ATIII concentrate, FFP(highest conc) followed by heparin. • Polycythemia- defect in platelet function, usually thrombotic, but can bleed. Keep HCT<48, PLTS<400 before SX. TX: ASA. Hypercoagulability • Lupus Anticoagulant- antiphospholipid antibodies. Not all patients have SLE. A procoagulant (prolonged PTT but hypercoagulable). • Diagnose by seeing prolonged PTT, false positive RPR test for syphilis. • TX: heparin, warfarin. Hypercoagulability • Cardiopulmonary Bypass- factor XII activated, results in hypercoagulable state. TX: heparin, warfarin. • Warfarin induced skin necrosis- Occurs when coumadin started before heparin. Due to a decrease in protein S,C making patient transiently hypercoagulable. Patients with Protien C deficiency highly susceptible. Hypercoagulability • May be genetic or acquired • Genetic mutations in the factor V gene – Mutant factor V is resistant to anticoagulant effect of activated protein C • Smoking, obesity and age • Late pregnancy and postpartum – amniotic fluid infusion into circulation • Disseminated cancers – tumors release procoagulants • Advanced age, bed rest and immobilization Hematologic Drugs • Warfarin- prevents Vit K dependent decarboxylation of glutamic residues on Vit K dependent factors. • Dextran- inhibits platelets and coagulation factors. • Sequential compression devices-improve venous return but also induce fibrinolysis with compression (release of tPA). Hematologic Drugs • Heparin- activates antithrombin III. • Reversed with protamine (1-1.5 protamine per 100u of heparin). • Half-life 60-90 min. • Long term heparin use causes osteoporosis, alopecia. Does not cross BBB. • Protamine side-effects are hypotension, bradycardia, decreased heart function. Hematologic Drugs • Hirudin- leeches, thrombin inhibitor. • Ancrod- Malayan pit viper venom, stimulates tPA release. • Amicar-antifibrinolytic, procoagulant, inhibits plasmin. Used in DIC, persistent bleeding following CABG, thrombolytic overdoses. • Streptokinase, tPA-need to follow fibrinogen levels, levels<100 associated with severe bleeding. Fate of thrombus • Propagation – Accumulate more platelets and fibrin and obstruct a critical vessel • Embolization – Dislodge thrombi and transported to other sites in vasculature Fate of thrombus, continued • Dissolution/resolution – Removed by fibrinolytic activity • Organization – Induce inflammation and fibrosis and may reopen and allow blood flow Fates continued • Recanalization – Openings and even blood vessels created in thrombus